This report incorporates former reports AA000210-10 and AA000200-02. The following projects are being conducted by CATE. Each study employs a number of dependent measures that are designed to study pathology and measure treatment efficacy. 1.) Clinical trial of SR141716, Rimonabant, to reduce voluntary ethanol consumption: The main endocannabinoid receptor subtype, the CB1 receptor, is widely distributed in the brain. Endocannabinoids act presynaptically in the CNS to modulate the release of various neurotransmitters such as dopamine, GABA, and glutamate. In the limbic forebrain, they are involved with motivational aspects of feeding such as desire and reward. Based on an extensive animal literature implicating the endocannabinoid system in alcoholism, we investigated whether the CB1 cannabinoid receptor antagonist rimonabant, compared to placebo, would reduce alcohol consumption in heavy drinkers. The results of this study have been published in Psychopharmacology, 2010. 2.) Pharmacologically-induced alcohol craving in detoxified alcoholics: Craving is a key element in the relapse process;therefore, craving is an important surrogate marker that can be used to evaluate the potential effectiveness of medications to treat alcohol dependent patients. A valid model of pharmacologically-induced alcohol craving might be useful to predict the efficacy of new pharmacotherapys for alcoholism, thereby accelerating drug development. To develop such a model, we tested two pharmacological challenges against a clinically established drug (acamprosate) for the treatment of alcoholism. In this protocol, we utilized a double-blind, placebo-controlled paradigm in which we administered: 1) an alpha 2-adrenergic antagonist (Yohimbine) which reliably induces reinstatement of alcohol seeking behavior in experimental animals, 2) a serotonergic compound (mCPP) which robustly increases alcohol craving in human alcoholics, and 3) placebo. Recruitment was completed this year. Data indicates that acamprosate did not affect the pharmacologically induced craving elicited by Yohimbine or mCPP. We are currently preparing a manuscript for publication. 3.) Effect of Acamprosate on CNS hyperexcitability in alcohol withdrawal: Clinical as well as preclinical studies indicate that the process of developing alcohol dependence involves a hyperglutamatergic state, which is thought to be a signal for emotional deregulations leading to craving and relapse, as well as neurotoxicity leading to cognitive impairment and loss of brain grey matter in alcoholic patients. Preclinical data indicate that acamprosate might be a useful agent to target the hyperglutamatergic state that develops during recurring episodes of withdrawal. The primary objective of this protocol was to evaluate the effects of acamprosate administration on brain glutamate/glutamine concentrations, as measured by MRS proton spectroscopy and CSF indices. Participant accrual has been completed. Results show the MRS measures of central glutamate are reduced across time when acamprosate therapy is initiated at the onset of alcohol abstinence. A manuscript has been accepted for publication in Archives of General Psychiatry. 4.) Effect of Naltrexone on Craving and Ethanol-Induced Brain Activity: Findings from animal and human studies indicate that the rewarding properties of ethanol arise in part from a complex interaction between alcohol, endogenous opioids, and dopamine (DA) systems. Naltrexone (NTX), an opioid receptor antagonist, has been studied widely in both preclinical and clinical research for the treatment of alcoholism. Numerous clinical studies have shown that short-term use of NTX in alcohol-dependent patients effectively prevents relapse and reduces the level of craving. This protocol is the first study which involves administering IV alcohol to treatment-seeking alcohol dependent patients. Following detoxification, patients are randomized, using a double-blind design, to receive NTX or placebo throughout the course of their hospitalization. fMRI scans involving ethanol infusions are performed to investigate the effects of Naltrexone on the blood oxygen level dependent response. Patient recruitment continues for this protocol. The ethical consideration of administering alcohol to treatment seeking alcoholics has resulted in a related publication. On-going studies are in progress to determine the effect of IV alcohol administration on relapse frequency. 5.) Effect of NK1R Antagonism on Alcohol Craving and PTSD Symptoms in Alcohol Dependent Patients with PTSD: Alcoholism is highly co-morbid with post traumatic stress disorder (PTSD). Since stress and negative affective states are major relapse triggering factors for alcohol use, the negative symptoms associated with PTSD are thought to promote alcohol dependence. Substance P, which is released in the amygdala in response to stress and acts at NK1 receptors (NK1Rs) to mediate behavioral stress responses. Blockade of the NK1R represents a novel approach for anti-stress actions. The present study is intended to determine whether the NK1R is a candidate target for treating civilian and military patients with alcohol dependence and PTSD. We are currently recruiting patients for this protocol. 6.) Clinical Studies Investigating Aggressive Behaviors in Alcohol Dependent Patients: To better understand the relationship between alcohol and aggression, we studied a subpopulation of alcoholics who had a history of perpetrating acts of domestic violence (DV). The rational for this is based on the fact that 70% to 80% of perpetrators of DV have an alcohol problem and secondly, most perpetrators report that when they consume alcohol they are more likely to become aggressive. Since serotonin modulates mood and responsiveness to environmental stimuli, we hypothesized that fluoxetine would be more effective than placebo in decreasing measures of aggression and anxiety in perpetrators of DV. To test this hypothesis, we conducted an outpatient study comparing the effectiveness of fluoxetine versus placebo on measures of irritability and aggression in a select group of alcoholic perpetrators of DV. Structural MRI and fMRI scans were used to characterize brain morphology and function. Patient accrual has been completed, brain MRI scans have been processed, and fMRI scans are being analyzed. A manuscript has been published in the Journal of Clinical Psychiatry and another manuscript is nearing completion. 7.) Collaborative project with NIMH: Imaging Cannabinoid CB1 Receptors in Patients with Alcohol Dependence: The brain endocannabinoid (EC) system involves endogenous cannabinoid agents (ECs) that act upon specific receptors (CB1 and CB2). ECs and CB1 receptors appear to modulate the brain reward system. During chronic alcohol exposure, EC levels in the brain are elevated and CB1 receptor levels are consequently reduced;this appears to be reversible following withdrawal. To what extent ECs and CB1 receptors are involved in the pathophysiology of alcohol dependence in humans is currently unknown. In this protocol, we utilize positron emission tomography to explore CB1 receptor abnormalities at various stages of alcohol withdrawal in humans. We are currently recruiting patients for this study.